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Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients

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Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients cancers Article Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients Takeji Umemura 1,2,3,* , Satoru Joshita 1 , Hiromi Saito 1, Shun-ichi Wakabayashi 1, Hiroyuki Kobayashi 1, Yuki Yamashita 1 , Ayumi Sugiura 1 , Tomoo Yamazaki 1 and Masao Ota 1 1 Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; [email protected] (S.J.); [email protected] (H.S.); [email protected] (S.-i.W.); [email protected] (H.K.); [email protected] (Y.Y.); [email protected] (A.S.); [email protected] (T.Y.); [email protected] (M.O.) 2 Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto 390-8621, Nagano, Japan 3 Department of Life Innovation, Shinshu University, Matsumoto 390-8621, Nagano, Japan * Correspondence: [email protected]; Tel.: +81-263-37-2634; Fax: +81-263-32-9412 Simple Summary: Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular Citation: Umemura, T.; Joshita, S.; carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the Saito, H.; Wakabayashi, S.-i.; KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a Kobayashi, H.; Yamashita, Y.; Sugiura, median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA A.; Yamazaki, T.; Ota, M. or HLA-Bw4 may influence the risk of cancer development. Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Abstract: Natural killer cells are partially mediated through the binding of killer cell immunoglobulin- Carcinoma in Hepatitis C Virus like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined Cirrhotic Patients. Cancers 2021, 13, the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated 3267. https://doi.org/10.3390/ hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cancers13133267 cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations Academic Editors: Paola Vacca, between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Laura Chiossone and Cox proportional hazards model with the stepwise method. During a median follow-up period of Emanuela Marcenaro 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio Received: 20 April 2021 (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, Accepted: 25 June 2021 p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)— Published: 29 June 2021 1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for Publisher’s Note: MDPI stays neutral developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with regard to jurisdictional claims in with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest published maps and institutional affil- KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC iations. development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset. Keywords: cirrhosis; hepatitis C virus; hepatocellular carcinoma; human leukocyte antigen; killer Copyright: © 2021 by the authors. cell immunoglobulin-like receptors; natural killer cells Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons 1. Introduction Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Chronic hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and 4.0/). hepatocellular carcinoma (HCC) [1,2], the latter of which is prominently involved in cancer- Cancers 2021, 13, 3267. https://doi.org/10.3390/cancers13133267 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3267 2 of 10 related death [3,4]. In Japan, HCV-related HCC accounts for approximately 60% of all HCC cases [5]. The mechanisms related to the progression of HCV infection to HCC include viral, environmental, and host genetic factors [6,7]. Natural killer (NK) cells are innate lymphocytes that are crucial for the early control of several pathogenic infections and malignancies [8]. NK cells express a wide repertoire of activating and inhibitory killer cell immunoglobulin-like receptors (KIR), which detect the expression levels of major histocompatibility complex class I ligands on normal and diseased cells in humans [9]. The expression of cognate human leukocyte antigen (HLA) class I molecules on target cells results in the inhibition of NK cell-mediated cytolysis via inhibitory KIR molecules, whereas the absence or aberrant presentation of these molecules leads to the activation of NK cells via KIR and other activating receptors [10]. KIR2DL1 recognizes HLA-C group 2 (HLA-C2) allotypes that share lysine at position 80, while KIR2DL2 and KIR2DL3 are specific for HLA-C group 1 (HLA-C1) allotypes having as- paragine at position 80 [11]. KIR3DL1 binds with higher affinity to HLA-Bw4 molecules containing isoleucine at position 80 (Bw4-80I) than to HLA-Bw4 molecules with threonine at position 80 (Bw4-80T) [12]. Similar to HLA molecules, KIR is highly polymorphic, which profoundly influences KIR–HLA interactions. These structural complexities, as well as extensive gene homology, have resulted in poor coverage using genome-wide association study methods, making KIR understudied as a cancer susceptibility trait. Gene content variability at the KIR locus has been investigated as a susceptibility trait in a variety of infectious and autoimmune diseases [10]. The interactions between independently segregating KIR and HLA genes on the biologic function of NK cells have also been described for melanoma [13,14]. We previously examined the role of KIR–HLA in HCV-related HCC in a cross-sectional study and revealed that KIR2DL1 + HLA-C1 was associated with younger onset (<65 years old) HCV-related HCC [15]. Other cross-sectional studies have demonstrated relationships between KIR–HLA and HCV-related HCC [16,17], although none have addressed the development of HCC in HCV patients over long-term follow-up. As cirrhosis is one the strongest risk factors for HCC development [2], the present study investigated the risk of HCC based on KIR–HLA pairs in patients with compensated HCV-associated cirrhosis. 2. Results 2.1. Patient Characteristics The cohort’s characteristics are summarized in Table1. Median age was 64 years and 52% of subjects were male. The median follow-up period was 6.6 years (interquartile range: 4.1–10.0). HCV genotype 1 was detected in 180 (85.3%) patients and genotype 2 was identified in 22 (14.7%) patients. The Child–Pugh–Turcotte score was A in all subjects. Although 94 patients (44.5%) had been treated with interferon-based therapy, none achieved a sustained virological response (SVR). During the observation period, 147 (69.7%) of 211 patients exhibited HCC, with a 5-year cumulative incidence of 26.3% and a 10-year cumulative incidence of 69.7%. The HCC group had a significantly higher male ratio as compared with the non-HCC group. The α-fetoprotein (AFP) was significantly higher, while albumin, platelet count, and PT% were significantly lower in patients with HCC than in those without. Table 1. Demographic and clinical characteristics of patients with hepatitis C virus (HCV)-induced liver cirrhosis. Patients with Hepatocellular Total Patients without HCC Characteristic Carcinoma (HCC) p-Value (n = 211) (n = 64) (n = 147) Age, y 64 (46–78) 63 (46–77) 65 (45–80) 0.110 Male, n (%) 110 (52.1) 84 (57.1) 26 (40.6) 0.027 Body Mass Index 22.3 (17.6–29.8) 22.2 (17.7–29.7) 22.6 (17.2–33.5) 0.417 Cancers 2021, 13, 3267 3 of 10 Table 1. Cont. Patients with Hepatocellular Total Patients without HCC Characteristic Carcinoma (HCC) p-Value (n = 211) (n = 64) (n = 147) Albumin, g/dL 3.8 (3.0–4.5) 3.8 (2.9–4.5) 4.1 (3.1–4.5) 0.009 Bilirubin, mg/dL 0.9 (0.5–1.8) 0.9 (0.5–1.8) 0.9 (0.4–1.9) 0.532 ALT, IU/L 55 (20–200) 56 (21–209) 54 (17–201) 0.177 Platelet count, ×109/L 10.6 (4.8–21.6) 10.2 (4.8–21.1) 12.0 (5.0–22.4) 0.033 Prothrombin time % 84.7 (62.3–108.0) 84.7 (58.4–104.9) 84.8 (67.9–113.1) 0.031 α-fetoprotein, ng/mL 6.9 (1.5–41.8) 9.2 (1.8–44.3) 3.7 (1.2–30.8) <0.001 Des-gamma-carboxy prothrombin, 18.0 (9.5–40.0) 19.0 (9.2–40.9) 13.0 (8.2–37.6) 0.015 mAU/mL HCV RNA, log IU/mL 6.5 (3.4–7.3) 6.5 (3.3–7.3) 6.4 (4.0–7.4) 0.838 HCV genotype 1, n (%) 180 (85.3) 125 (85.0) 55 (85.9) 0.865 Interferon treatment, n 94 (44.5) 67 (45.6) 27 (42.2) 0.649 (%) Parameters are presented as the median (5th–95th percentiles) for continuous variables and the total number (%) for categorical variables.
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